CD6 is a T-cell costimulatory molecule expressed on developing thymocytes and on mature T-cells. We hypothesize that a major role of CD6 is to co-stimulate thymocytes and mature T-cells during low functional acidity interactions with MHC/antigen complexes. Over- expression of CD6 in transgenic mice is hypothesized to lead to alteration of the phenotype and function of both thymocytes and mature lymphocytes. The focus of this application is to determine the function of CD6 in thymocyte selection and antigen responses of mature T-cells. Our specific aims are: 1) To characterize the phenotype of our new transgenic mice that express human CD6 and over-express total CD6 2) To test the hypothesis that in the thymus, CD6- dependent co-stimulation increases thymocyte selection; 3) To test the hypothesis that in the periphery, CD6-dependent co-stimulation of mature T-cells fine tunes their response to specific antigen. Expression of CD6 may contribute to autoimmunity through increased selection of self-reactive thymocytes, increased resistance and/or nature T-cells to apoptosis, and decreases in the stimulation threshold of mature T-cells to self-antigens. To define the function(s) o CD6 we will use complimentary "gain of function" and "loss of function" approaches, including mice bred either to lack or to over-express CD6, in combination with antigen-specific TCR transgenic mice, thymic organ cultures, and specific soluble reagents which inhibit CD6/CD6 ligand interactions. Our long-term goal is to understand the role of CD6 in autoimmunity. One of the major problems in the treatments of autoimmunity is that current therapies reduce both autoimmunity and protective immunity simultaneously. We ultimately want to determine if inhibiting CD6/CD6L interactions can selectively inhibit reactivity with weaker self-antigens without compromising responses to stronger exogenous antigens that are important in innate immunity.